Despite our rapidly growing understanding of how oncogenes signal, relatively little is known about the underlying mechanisms that cause abrupt cell cycle arrest, cell death and tumor regression upon acutely inactivating an oncogene. This application seeks to address NIH's Provocative Question #22: Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene? We propose that acute inactivation of different oncogenes in diverse tissue types results in a common 'metabolic catastrophe.' Acute inhibition of driver oncogenes results in widespread collapse of tumor-associated metabolic reprograming. The resulting metabolic state of tumor cells can neither supply them with sufficient energy nor metabolic intermediates for anabolism resulting in a state of 'metabolic catastrophe' resulting in tumor cell death and regression of cancers. The aims of the application seek to: 1) Use innovative hyperpolarized 13C-pyruvate imaging to visualize the earliest metabolic events associate with tumor regression. 2) We will perform global gene expression and metabolomic profiling of liver cancers driven by MYC, RAS or MYC and RAS together to define metabolic pathways altered as a consequence of acute oncogene inactivation. 3) We will compare the metabolic consequences of oncogene inactivation in diverse tissue types, including breast, lung and liver tumors to define which oncogene-regulated metabolic pathways are common across different tissue types and driver oncogenes. The overarching goal of these studies is to identify metabolic pathways critical for tumor survival, against which novel therapeutics can be developed. PUBLIC HEALTH RELEVANCE: A major unanswered question in cancer biology is why and how tumors regress when the initiating oncogene is acutely inhibited. This application seeks to answer this question by examining diverse metabolic changes which occur when different oncogenes are acutely inactivated. We will test the effects of inactivating two canonical oncogenes, MYC and RAS and both combined, in breast lung and liver tumor tissues. An innovative approach to study tumor formation and regression will be employed; including novel imaging technology as well as genetic and metabolic profiling of diverse tumor types. We anticipate that knowledge gained from these studies will be rapidly translated to the development of novel therapeutics to target human cancer.